Integrated characterization of the human chemoreflex system controlling ventilation, using an equilibrium diagram

Abstract

The chemoreflex system controlling ventilation consists of two subsystems, i.e., the central controller (controlling element), and peripheral plant (controlled element). We developed an integral framework to quantitatively characterize individual ventilatory regulation by experimental determination of an equilibrium diagram using a modified metabolic hyperbola and the CO2 response curve. In 13 healthy males, the steady-state arterial CO2 pressure (P(a)CO2) and minute ventilation (V(E)) were measured. To characterize the central controller, we changed fraction of inspired CO2 (0, 3.5, 5 and 6% CO2 in 80% oxygen with nitrogen balance) and measured the P(a)CO2-V(E) relation. To characterize the peripheral plant, we altered V(E) by hyper- or hypoventilation using a visual feedback method, which made it possible to control both tidal volume and breathing frequency, and measured the VE-P(a)CO2 relation. The intersection between the two relationship lines gives the operating point. The relationship between P(a)CO2 and V(E) for the central controller was reasonably linear in each subject (r2 = 0.808-0.995). The peripheral plant approximated a modified metabolic hyperbolic curve (r = 0.962-0.996). The operating points of the system estimated from the two relationship lines were in good agreement with those measured under the closed-loop condition. The gain of the central controller was 1.9 (1.0) l min(-1) mmHg(-1) and that of the peripheral plant was 3.0 (0.5) mmHg l(-1) min(-1). The total loop gain, the product of the two gains, was 5.3 (2.5). We conclude that human ventilatory regulation by the respiratory chemoreflex system can be quantitatively characterized using an equilibrium diagram. This framework should be useful for understanding the mechanisms responsible for abnormal ventilation under various pathophysiological conditions.